Trans-chalcone activity against Trichophyton rubrum relies on an interplay between signaling pathways related to cell wall integrity and fatty acid metabolism

BMC Genomics

Rene Oliveira Beleboni¹  Igor Sawasaki Moreli¹  Mozart Marins¹  Ana Lúcia Fachin¹  Bruna Aline Micheloto Cantelli¹  Matheus Eloy Franco²  Tamires Aparecida Bitencourt³  Marina Campos Rocha⁴  Iran Malavazi⁴  Pablo Rodrigo Sanches⁵  Claudia Macedo⁵  Geraldo Aleixo Passos⁵ 

[1] 0000 0000 8810 9529, grid.412281.c, Unidade de Biotecnologia, Universidade de Ribeirão Preto, Av: Costábile Romano 2201, 14096-900, Ribeirão Preto, SP, Brazil;0000 0000 8810 9529, grid.412281.c, Unidade de Biotecnologia, Universidade de Ribeirão Preto, Av: Costábile Romano 2201, 14096-900, Ribeirão Preto, SP, Brazil;0000 0004 0388 4008, grid.472932.9, Instituto Federal do Sul de Minas - Campus Machado, Machado, Brazil;0000 0000 8810 9529, grid.412281.c, Unidade de Biotecnologia, Universidade de Ribeirão Preto, Av: Costábile Romano 2201, 14096-900, Ribeirão Preto, SP, Brazil;0000 0004 1937 0722, grid.11899.38, Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil;0000 0001 2163 588X, grid.411247.5, Departamento de Genética e Evolução, Centro de Ciências Biológicas e da Saúde (CCBS), Universidade Federal de São Carlos, São Carlos, Brazil;0000 0004 1937 0722, grid.11899.38, Departamento de Genética, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil;

关键词: Chalcone;    CWI;    Elastin;    Keratin;    Dermatophyte;    Transcriptional profile;   

DOI  :  10.1186/s12864-019-5792-0

来源: publisher

【 摘 要 】

BackgroundTrichophyton rubrum is the main etiological agent of skin and nail infections worldwide. Because of its keratinolytic activity and anthropophilic nature, infection models based on the addition of protein substrates have been employed to assess transcriptional profiles and to elucidate aspects related to host-pathogen interactions. Chalcones are widespread compounds with pronounced activity against dermatophytes. The toxicity of trans-chalcone towards T. rubrum is not fully understood but seems to rely on diverse cellular targets. Within this context, a better understanding of the mode of action of trans-chalcone may help identify new strategies of antifungal therapy and reveal new chemotherapeutic targets. This work aimed to assess the transcriptional profile of T. rubrum grown on different protein sources (keratin or elastin) to mimic natural infection sites and exposed to trans-chalcone in order to elucidate the mechanisms underlying the antifungal activity of trans-chalcone.ResultsOverall, the use of different protein sources caused only slight differences in the transcriptional profile of T. rubrum. The main differences were the modulation of proteases and lipases in gene categories when T. rubrum was grown on keratin and elastin, respectively. In addition, some genes encoding heat shock proteins were up-regulated during the growth of T. rubrum on keratin. The transcriptional profile of T. rubrum exposed to trans-chalcone included four main categories: fatty acid and lipid metabolism, overall stress response, cell wall integrity pathway, and alternative energy metabolism. Consistently, T. rubrum Mapk was strongly activated during the first hours of trans-chalcone exposure. Noteworthy, trans-chalcone inhibited genes involved in keratin degradation. The results also showed effects of trans-chalcone on fatty acid synthesis and metabolic pathways involved in acetyl-CoA supply.ConclusionOur results suggest that the mode of action of trans-chalcone is related to pronounced changes in fungal metabolism, including an imbalance between fatty acid synthesis and degradation that interferes with cell membrane and cell wall integrity. In addition, this compound exerts activity against important virulence factors. Taken together, trans-chalcone acts on targets related to dermatophyte physiology and the infection process.

【 授权许可】

CC BY